The protein folding is the process by which proteins their three-dimensional structure maintained. It takes place during and after the synthesis of the peptide chain and is a prerequisite for the protein to function properly. The folding is caused by the smallest movements of the solvent molecules (water molecules) and by electrical forces of attraction within the protein molecule. Some proteins can only fold properly with the help of certain enzymes or chaperone proteins.
Proteins are synthesized on the ribosomes as linear polypeptide chains from amino acids . The sequence of the individual amino acids forms the primary structure of the protein. During or after the synthesis, the polypeptide chain folds into a defined spatial structure ( tertiary structure ) made up of smaller structural elements ( secondary structure ). Some proteins consist of more than one polypeptide chain. If such an oligomer is formed from several polypeptide chains in a tertiary structure, one speaks of a quaternary structure . The primary structure consists of amino acids covalently linked by peptide bonds . The protein folding results from the bonds and forces that continue to act ( ionic , polar and Van der Waals interactions , hydrogen bonds , hydrophobic effects ) between different atoms; in individual cases the secondary, tertiary and quaternary structure becomes through covalent bonds after translation stabilized like disulfide bridges and isopeptide bonds .
During the folding process, the amino acid chain adopts the native conformation , i.e. the biologically functional conformation, in a fraction of a second . This process is known as the Levinthal Paradox . The fully folded protein usually has the lowest possible Gibbs energy ( Anfinsen dogma ). The exact process of protein folding has not yet been clarified and is a current research subject in biochemistry. With some proteins, the folding takes place via an intermediate state called molten globule . The hydrophobic amino acid residues are agglomerated by hydrophobic collapse , with all secondary structural elements being formed within a few milliseconds. Only then does the tertiary structure develop, which can take a few seconds.
Often, newly synthesized proteins cannot fold themselves correctly, so folding helpers are required. By accumulation, chaperones prevent premature protein folding and thus aggregation during protein synthesis . Chaperonins can enclose peptide sequences like in a barrel and help fold through ATP.
Protein disulfide isomerases can correct incorrectly formed disulfide bridges . Peptidyl-prolyl- cis / trans -isomerases help to convert proline from the cis -configuration to a trans -configuration. Most of the other amino acids are always in the trans configuration.
Structure and function
The specific function of a protein is only possible through its defined structure. Misfolded proteins are normally recognized as part of protein quality control and broken down in the proteasome . If this breakdown fails, protein accumulations occur which, depending on the protein, can trigger various diseases in which mutations prevent correct folding. These are known as protein misfolding disorders and can be caused by:
- The protein stopped working. Examples: Forms of cancer that go back to mutations in the protein p53 .
- The protein aggregates . Examples: sickle cell anemia in which hemoglobin aggregates; Alzheimer's Disease ; Parkinson's Disease ; Huntington's disease .
- The protein is toxic. Example: BSE caused by the prions .
When folding, the protein takes on the native (structured or biologically functional) state. The reverse process is called denaturation . Folding and denaturation of proteins resemble first-order phase transitions, i.e. extensive parameters such as volume and heat energy change abruptly. The denaturation of proteins is triggered , for example, by heat, extreme pH conditions or extreme salt concentrations.
In 1972 Christian B. Anfinsen received the Nobel Prize in Chemistry for the observation that after denaturation, small proteins can fold back into their native form as soon as they are exposed to ambient conditions in which they are stable. Anfinsen concluded from this observation that the native structure of every protein is determined by its amino acid sequence. Rare metamorphic proteins such as lymphotactin , which have two fundamentally different secondary structures, are an exception .
The first comprehensive theory of protein folding was developed by the Chinese scientist Hsien Wu in the 1920s . In the European-American area, the first essential work was carried out by Christian B. Anfinsen (Nobel Prize in Chemistry 1972) and Charles Tanford ( Tanford transition ) in the 1950s.
The “ Folding @ home ” project at Stanford University is currently running to simulate these folds, and Internet users can help by making computing power available. The projects “ POEM @ home ” of the University of Karlsruhe and “ Rosetta @ home ” of the University of Washington also pursue this goal. All three projects use different approaches to simulate protein folding. The computer game Foldit takes a further approach , in which the players try to fold a protein as skilfully as possible and thus bring it to a low energy level.
Furthermore, the joint experiment CASP takes place every two years , which offers research groups the opportunity to test the quality of their methods for predicting protein structures based on the primary structure and to get an overview of the current status in this research area.
So far there are two scientifically recognized models for protein folding:
- Diffusion-collision model , in which a protein core (nucleus) is formed first and then the secondary structure;
- Nucleation-condensation model in which the secondary and tertiary structure are formed simultaneously.
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